CD4 is a surface molecule of human helper T-lymphocytes that serves as the receptor for human immunodeficiency virus (HIV), the causative agent of AIDS. We have focused on two areas related to CD4 and HIV: 1) Design of CD4-based therapeutics for the treatment individuals infected with HIV. We have continued to study a genetically engineered hybrid toxin (CD4-PE40) which is targeted to selectively kill HIV-infected cells. Extending previous findings with continuous human T-cell lines, we have found that the hybrid toxin is active against HIV-infected primary T-cells, as well as against infected cells of the monocyte/macrophage lineage (continuous lines and primary cells). Most importantly, CD4-PE40 shows highly synergistic anti-HIV activity with reverse transcriptase inhibitors (AZT, DDI), in both continuous T-cell lines and primary T-cell cultures. We observed that combination treatment with CD4-PE40 plus AZT can completely eliminate infectious HIV from cultures of continuous T-cell lines. 2) Structure/function studies of the interaction of CD4 with the HIV-1 envelope glycoprotein (gp120/gp41 complex). The focus of this work is to identify structural changes in the envelope glycoprotein which occur upon CD4 binding, and which are involved in virion fusion with the cell membrane. Soluble CD4 was found to promote specific dissociation of gp120 from the envelope glycoprotein complex. Studies with synthetic peptides and soluble CD4 molecules from other species indicate that this dissociation effect may involve a region within the first domain of the CD4 molecule, distinct from the region previously implicated in high affinity binding to gp120. We are developing strategies to determine whether this structural change is associated with exposure of the presumed fusagenic N-terminus of the gp4l molecule.